N-(tertiary-aminoalkyl)-2-substituted-4-nitrobenzamides and their salts



Patented Oct. 5, 1954 UNITED STATES ATENT OFFICE N-(TERTIARY AMINOALKYL) 2 SUBSTI- TUTED-4-NITROBENZAMIDES AND THEIR SALTS Raymond 0. Clinton, North Greenbush, and Stanley C. Laskcwski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application May 21, 1953, Serial No. 356,594

11 Claims.

( O NH-X-NR R1 where R2 is a member of the group consisting of H and lower alkyl radicals, X is a lower alkylene radical and NRR1 is a tertiary-amino radical. Some of these compounds have pharmacological properties, for instance, the quaternary salts have ganglionic blocking activity; and all of these compounds are useful for the preparation of our corresponding i-amino compounds which are disclosed and claimed in our copending application Serial No. 218,532, filed March 30, 1951, of which this application is a continuation-in-part.

In the above general formula, the lower alkyl radical represented by R2 has preferably 1-6 carbon atoms, including such examples as methyl, ethyl, n-propyl, isobutyl, 2-butyl, 3-amyl, n-hexyl, and the like. The lower alkylene radical designated hereinabove as X has preferably 2-4 carbon atoms and has its two free valence bonds on different carbon atoms. Thus, X includes such examples as CH2CH2, -CH2CH2CH2,

and the like. The tertiary-amino radical shown above as NRR1 comprehends lower dialkylamino radicals where R and R1 are lower alkyl groups, alike or difierent, and each alkyl group having preferably 1-6 carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiary-amino radical designated as NRR1 encompasses those radicals where R and R1 are joined directly or through an oxygen atom to form saturated N-heteromonocyclic radicals having 5-6 ring atoms, illustrated by examples such as 1piperidyl, Z-methyI-I-piperidyl, 3-ethyl-lpiperidyl, i-methyl-l-piperidyl, 2,6-dimethyl-lpiperidyl, 1-pyrrolidyl, 2-methyl-l-pyrrolidyl, 2,5- dimethyl-l-pyrrolidyl, 4-morpholinyl, and the like.

2 The amides of our invention areconveniently prepared from the corresponding 4-nitro-2-substituted-benzoic acids as illustrated by the following equation, wherein R, R1 and R2 have the meanings given hereinabove:

OR; OR:

' t C O OH ONH--XNRR1 The intermediate 4-nitro-2-alkoxybenzoic acids (designated above as (A) where R2 is alkyl) and their lower alkyl esters are disclosed but not claimed in our copending U. S. patent applications Serial Nos. 168,843 and 168,844, now U. S. Patent 2,657,209, filed June 1'7, 1950.

A specific illustration of the above preparation when R2 is H is the conversion of 4-nitro-2- hydroxybenzoic acid into N-[3-(1-piperidyl)- propyl]-4-nitro-2-hydroxybenzamide. In practicing our invention we preferably ran this reaction by first converting 4-nitro-2-hydroxybenzoic acid into its lower alkyl ester, e. g., methyl ester, and then treating the lower alkyl ester with a tertiary-aminoalkylamine having the formula H2NXNRR1.

A specific illustration of the above reaction when R2 is a lower alkyl radical is the conversion of 4-nitro-2-ethoxybenzoic acid into N- (2-diethylaminoethyl) -4-nitro 2 ethoxybenzamide. This reaction was preferably carried out by converting the 4-nitro-2-alkoxybenzoic acid into its corresponding acid halide by treating with an appropriate halogenating agent such as thionyl chloride and treating the resulting acid halide with a tertiary-aminoalkylamine having the formula H2N-X--NRR1.

Our invention includes, also, salts of the basic amides described above. Such salts include nontoxic acid addition salts and quaternary ammonium salts, which are readily prepared from the basic amides. Acid addition salts are formed by reacting the basic amides with an acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, lactic acid, citric acid, tartaric acid, ethanesulfonic acid, etc., to yield, respectively, the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, sulfamates, acetates, lactates, citrates, tartrates, ethanesulfonates, etc. Our quaternary ammonium salts are prepared by treating the N-(tertiary-ammualkyl) -4-nitro-2- hydroxy(or alkoxy)benzamides (B) with lower alkyl and aralkyl esters of strong inorganic acids and organic sulfonic acids, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, propyl bromide, propyl iodide, benzyl chloride, benzyl bromide, methyl sulfate, ethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, etc. yielding, respectively, the methochlorides, methobromides, methiodides, ethobromides, ethiodides, propobromides, propiodides, benzochlorides, benzobromides, methosulfates, ethosulfates, methobenzenesulfonates, metho-p-toluenesulfonates, etc.

The following examples further illustrate our invention, but should not be construed as a limitation thereto.

EXAMPLE 1 N-(Z-diethylaminoethyl) -4-mtr0-2- hydroxybenzamide A solution of 16.7 g. of ethyl 4-nitro-2-hydroxybenzoate and 23.2 g. of 2-diethylaminoethylamine in 250 cc. of dry toluene was refluxed for eight hours. On cooling, the reaction mixture separated into two layers, the desired product being in the deep orange-colored lower layer, which solidified when rubbed. After the toluene had been removed by distilling under reduced pressure, the orange solid that remained was dissolved in a minimum quantity of hot absolute ethanol. The solution was diluted with n-pentane, cooled, and filtered. The solid was recrystallized from absolute ethanol-n-pentane, yielding the desired product, N-(2-diethylaminoethyl) -4-nitro-2-hydroxybenzamide.

This basic amide was converted into its hydrochloride salt by dissolving it in an excess of warm ethanol saturated with hydrogen chloride gas, warming the mixture to complete dissolution, cooling the solution and diluting it with absolute ether. Two recrystallizations of this yellow solid from absolute ethanol-absolute ether yielded N- (2 diethylaminoethyl) 4 nitro 2 hydroxybenzamide hydrochloride, M. P. 149.6-l50.2 C.

(cor.).

AnaZ.--Calcd. for C13H19N3O4.HC11 C, 49.13; H, 6.34; Cl, 11.16. Found: C, 49.35; H, 6.10; Cl, 11.12.

Additional N (tertiary aminoalkyl) 4- nitro 2 hydroxybenzamides which can be prepared according tothe foregoing procedure by substituting the appropriate tertiary-aminoalkylamine for 2-diethylaminoethy1amine include the following: N (2 dimethylamino 1 propy1)- 4 nitro 2 hydroxybenzamide; N (2 di nbutylaminoethyl) 4 nitro 2 hydroxybenzamide; N [3 (1 piperidyDpropyl] 4 nitro- 2 hydroxybenzamide; N [2 (2 methyl 1- piperidyl) ethyl] 4 nitro 2 hydroxybenzamide; N [3 (1 pyrrolidyhpropyll 4 nitro- 2 hydroxybenzamide; N [2 (2,5 dimethyl- 1 pyrrolidyl) ethyl] 4 nitro 2 hydroxybenzamide; and N [3 (4 morpholinyl)propy1l- 4-nitro-2-hydroxybenzamide.

EXAMPLE 2 N S-diethylaminopropyl) -4-mtro-2- hydroxybenzamide This preparation was carried out according to the procedure described above for Example 1, but using 16.7 g. of ethyl 4-nitro-2-hydroxybenzoate, 13.0 g. of 3-diethylaminopropylamine and 250 cc. of dry toluene. The product thus obtained was N (3 diethylaminopropyl) 4 nitro 2 hydroxybenzamide, which in the form of its hydro- 4 chloride, melted at 137.8-138.8 C. after recrystallization from isopropanol.

AnaL-Calcd. for C14H21N3O-;.HCl: C, 50.67; H, 6.68; N, 12.66. Found: C, 50.72; H, 6.50; N, 12.52.

EXAMPLE 3 N (4-diethylaminobutyl) -4-nitro-2- hydrozcybenzamzde When the procedure described above for Example 1 is followed, but using 39.4 g. of methyl 4-nitro-2-hydroxybenzoate, 43.2 g. of 4-diethylalninobutylamine and 500 cc. of dry toluene, there was obtained N (4 diethylaminobutyl) 4- nitro-2-hydroxybenzamide, which in the form of its hydrochloride melted at 146.0-146.9 C. when recrystallized from isopropanol.

AnaZ.-Calcd. for C15H2zNaO4.HCl: C, 52.09; H, 7.00; Cl, 10.25. Found: C, 52.23; H, 6.70; Cl, 10.09.

EXAMPLE 4 N (3-dzethylaminopropyl) -4-nitro-2- methoacybenzamz'de A mixture of 42.2 g. of methyl 4-nitro-2-methoxybenzoate, 39.1 g. of 3-diethylaminopropylamine in 500 cc. of dry xylene was refluxed for sixteen hours. The xylene was distilled off under reduced pressure, the residual oil was dissolved in a small amount of ethyl acetate, the solution was cooled and diluted with n-hexane whereupon an oily material separated. The solvents were decanted from the brown oily base, N-(3-diethylaminopropyl) 4 nitro 2 methoxybenzamide, which was converted into its hydrochloride by dissolving it in a small quantity of ethyl acetate and treating the resulting solution with an excess of ethereal hydrogen chloride whereupon there separated a brown oily material. The solvent was decanted and the oil was triturated with isopropanol and then diluted with absolute ether, yielding a semi-solid, but filterable, product which was filtered and recrystallized twice from isopropanol. There was thus obtained, as yellow rosettes of needles, N-(3-diethylaminopropyl) -4- nitro-Z-methoxybenzamide hydrochloride, M. P. 1491-1500 C. (cor.).

AnaZ.-Calcd. for C1sI-I23N3O4.HC1: C, 52.09; H, 7.00; Cl, 10.25. Found: C, 52.16; H, 6.88; Cl, 10.33.

Additional N (tertiary aminoalkyl) 4- nitro-2-alkoxybenzamides which can be prepared according to the above procedure using the appropriate lower alkyl 4-nitro-2-alkoxybenzoate and tertiary-aminoalkylamine in place of methyl 4 nitro 2 methoxybenzoate and 3 diethylaminopropylamine, respectively, include the following: N (2 dimethylamino 1 propyl) 4- nitro 2 methoxybenzamide; N (2 di nbutylaminoethyl) 4 nitro 2 methoxybenzamide; N [3 (1 piperidyDpropyl] 4 nitro- 2 ethoxybenzamide; and N [3 (2 methyl- 1 piperidyDpropyl] 4 nitro 2 methoxybenzamide.

EXAMPLE 5 N Z-diethylaminoethyl) -4-m'tro-2-methomybenzamide hydrochloride A mixture of 80.0 g. of 4-nitro-2-methoxybenzoic acid and 242 g. of thionyl chloride was refluxed for two hours and the excess thionyl chloride was removed by distilling in vacuo. The residue was taken up in dry benzene and the benzene was removed by distilling in vacuo and the remaining oily material was dried in a vacuum desiccator over phosphorus pentoxide. This material, thus obtained, was 4-nitro-2- methoxybenzoyl chloride.

A solution of 40 g. of 4-nitro-2-methoxybenzoyl chloride, 21.6 g. of Z-diethylaminoethylamine and 300 cc. of dry benzene was warmed, whereupon there separated a gummy material, which was triturated with warming until solidification resulted. The mixture was cooled in an icebath and diluted to a total volume of about one liter with benzene. The solid was filtered and recrystallized from absolute ethanolm-hexane, using decolorizing charcoal, yielding N (2 diethylaminoethyl) 4 nitro 2 methoxybenzamide hydrochloride, M. P. 161.2-162.7 C. (cor.).

Anal.-Calcd. for C1lI-I21NsO4.HCl: N, 4.22; C], 10.69. Found: N, 4.14; Cl, 10.49.

Additional N (tertiary aminoalkyl) 4- nitro-2-alkoxybenzamide hydrochlorides which can be prepared according to the above procedure by substituting the appropriate 4-nitro-2-alkoxy benzoic acid and tertiary-aminoalkylamine for 4 nitro 2 me'thoxybenzoic acid and 2 diethylaminoethylamine, respectively, include the following: N [2 (2 methyl l piperidyD- ethyl] 4 nitro 2 ethoxybenzamide hydrochloride; N [3 (1 pyrrolidyDprcpyl] 4- nitro 2 ethoxybenzamide hydrochloride; N- [2 (2,5 dimethyl l pyrrolidyl) ethyl] 4- nitro 2 methoxybenzamide hydrochloride; and N [3 (4 morpholinyDpropyl] 4 nitro 2- ethoxybenzamide hydrochloride.

EXAIVIPLE 6 N- (3-dieth1/Zamino-2-hydroarypropyl) -4-m'tro Z-methorybenzamz'de A mixture of 19.3 g. of 3 diethylamino 2- hydroxypropylamine, 16.6 g. of sodium bicarbonate and 125 cc. of water was stirred until a clear solution resulted. To this solution was added with stirring 28.4 g. of 4-nitro-2-methoxybenzoyl chloride in 309 cc. of chloroform at room temperature over a period of thirty-five minutes. The resulting solution was then stirred for an additional one hour at room temperature, dried over anhydrous calcium sulfate and the solvent removed by distilling in vacuo. There was thus obtained, as a dark brown, viscous oil, N-(3-diethylamino 2 hydroxypropyl) 4 nitro 2- methoxybenzamide.

Treatment of this basic amide in absolute ethanol solution with an excess of ethanolic hydrogen chloride (20% by weight) yielded, as an oil, the corresponding hydrochloride. The mixture was diluted with n-hexane to ensure complete precipitation of this salt. The oil was separated from the solvents by decantation and then was dissolved in absolute ethanol. To the ethanol solution was added n-hexane to turbidity, whereupon the hydrochloride precipitated in crystalline form. The crystalline product was filtered and recrystallized twice from absolute ethanol, yielding N- (3-diethylamino-Z-hydroxypropyl) -4-m'- tro-2-methoxybenzamide hydrochloride, M. P. 153.6155.0 C. (cor.).

Anal.-Calcd. for CH23N305.HC1: N(NO2), 3.87; Cl, 9.80. Found: N(N0 3.99; 01, 9.62.

EXAMPLE '7 N- (Z-diethylaminoethyl) -4-mtro-2-nbutomybenzamide To a mixture of 23.6 g. of 4-nitro-2-n-butoxybenzoic acid, 100 cc. of dry benzene and 9.48 g. of pyridine was added dropwise 9.53 g. of thionyl chloride dissolved in 100 cc. of dry benzene. The solution was then heated on a steam bath for ten minutes, yielding a solution of 4-nitro-2-nbutoxybenzoyl chloride.

This solution was added slowly, with stirring to a mixture of cc. of water, 15.1 g. of sodium bicarbonate, 11.6 g. of 2-diethylamino-ethylamine and 200 cc. of chloroform, and the resulting mixture was stirred for one hour. The chloroform and water layers were separated, the aqueous layer was washed with chloroform and the chloroform washings were added to the chloroform layer. The chloroform solution was then washed with water, 5% aqueous sodium hydroxide solution and water again, and then dried over anhydrous calcium sulfate. The chloroform was removed by distilling in vacuo, the remaining material was dissolved in 300 cc. of toluene and the toluene was removed by distilling in vacuo. The residue was then taken up in 300 cc. of benzene followed by removal of the benzene by distilling in vacuo, yielding a solid product. This solid material was recrystallized three times from n-heptane, yielding N-(Z-diethylaminoethyl)-4- nitro-2-n-butoxybenzamide, M. P. 49.9-50.9 C. (con).

Anal.Calcd. for C1'IH27N304I N, 12.45. Found: N, 12.32.

The basic amide was converted into its monohydrochloride by dissolving it in ethyl acetate and treating the resulting solution with an excess of hydrogen chloride dissolved in ether (20% by weight). Absolute ether was added to ensure complete precipitation of the hydrochloride, which separated as an oil. On cooling, the oily material gradually gummed and finally crystallized. Two recrystallizations of this material from absolute ethanol-n-hexane yielded N-(2-diethylaminoethyl)-4-nitro-2-n-butoxybenzamide hydrochloride, M. P. 133.2-134.2 C. (cor.).

Anal.Calcd. for C1'1H27N3O4.HC12 Cl, 9.48;

Nuvo 3.74; N, 11.24. Found: Cl, 9.57; Nuwop. 3.74; N, 11.33.

Additional N-(tertiary-aminoalkyl) -4-nitro-2- alkoxybenzamides which can be prepared according to the above procedure by substituting the appropriate 4-nitro-2-alk-oxybenzoic acid and tertiary-aminoalkylamine for 4-nitro-2-n-butoxybenzoic acid and Z-diethylaminoethylamine, respectively, include the following: N-(Z-dimethylamino 1 propyl) 4 nitro 2 n amoxybenzamide; N- Z-di-n-butylaminoethyl) -4-nitro-2- n-propoxybenzamide; N- [3-(1-piperidyl) propyl] 4-nitro-2nbutoxybenzamide; N- [2- (2-methyl- 1 piperidyl) ethyl] 4 nitro 2 n hexoxybenzamide; N-[3-(1-pyrrolidyl)propyll-4-nitro- 2- isobutoxybenzamide; N-[2-(2,5-dimethyl-1- pyrrolidyDethyl] 4 nitro 2 n propoxybenzamide; and N- [3- (4-morpholinyl) propyl] -4- nitro-2-n-butoxybenzamide.

EXANIPLE 8 N Z-diethylaminoethyl) -4-m'tro-2-npropoztybenzamzde When the procedure described above for Example was followed but substituting 22.5 g. of 4-nitro-2-n-propoxybenzoic acid in place of the 4-nitro-2-n-butoxybenzoic acid, there was obtained N- (2-diethylaminoethyl) -4-nitro-2-npropoxybenzamide, M. P. 64.4-65.0 C. (cor.) when recrystallized from n-heXane.

AnaL-Calcd. for C16H25N304I N, 12.99. Found: N, 13.28. 1

Conversion of the basic amide to its monohydrochloride was accomplished by dissolving it in ethyl acetate and treating the resulting solution with an excess of hydrogen chloride in ether (20% by weight). The precipitated salt was recrystallized twice from absolute ethanol, yielding N-(2- 7 diethylaminoethyl) 4 nitro 2 n propoxybenzamide hydrochloride, M. P. 164.8167.9 C. (con).

AnaZ.-Calcd. for C1sHz5NaO4.HCl: Cl, 9.85; Nmo 3.89. Found: Cl, 9.96; Nmo 4.14.

EXAMPLE 9 N- (Z-diethylaminoethyl) -4-mtro-2-nbutorybenzamide methiodide;

To a solution of N-(2-diethylaminoethyD-4- nitro-Z-n-butoxybenzamide in 75 cc. of ethyl acetate was added cc. of methyl iodide and the resulting solution was allowed to stand at room temperature. The precipitated quaternary salt was recrystallized twice from absolute ethanol, yielding N-(Z-diethylaminoethyl) -4-nitro-2- n-butoxybenzamide methiodide, M. P. 136.5-137.6 C. (Con).

, Anal.--Calcd. for C17Hz'1N304.CH3IZ Nmo 2.92; I, 26.48. Found: Nmo 3.09; I, 26.40.

Additional N- (tertiary-aminoalkyl) -4-nitro- 2-alkoxybenzamide quaternary salts which can be prepared according to the foregoing procedure by substituting the appropriate basic amide and an alkyl or aralkyl ester of a strong inorganic acid or an organic sulfonic acid for N- (Z-diethylaminoethyl)-4-nitro-2-n-butoxybenzamide and methyl iodide, respectively, include the following: N- (Z-dimethylamino-l-propyl) -4-nitro-2- n-amoxybenzamide methiodide; N- (2-di-n-butylaminoethyl) 4 nitro 2 n propoxybenzamide methobromide N- [3-(1-piperidy1) propyl] 4-nitro-2-n-butoxybenzamide ethiodide; N -[2- (2 methyl 1 piperidyDethyll 4 nitro 2- n-hexoxybenzamide benzobromide; N- [3-(1-pyrrolidyDpropyl] 4 nitro 2 isobutoxybenzamide methosulfate; N- [2- (2,5-dimethyl-1-pyrrolidyl)ethyl] 4 nitro 2 methoxybenzamide methobenzenesulfonate; and N-[3-(4- morpholinyDpropyl] 4 nitro 2 ethoxybenzamide metho-p-toluenesulfonate.

Similarly, following the foregoing procedure but using the related N-(tertiary-aminoalkyD- 4-nitro-2-hydroxybenzamides, as described in Example 1, the N-(tertiary-aminoalkyl) -4nitro- Z-hydroxybenzamide quaternary salts are formed, for example, N-(2-diethylaminoethyl)-4-nitro- 2-hydroxybenzamide methiodide, N-(2-di-nbutylaminoethyl) 4 nitro-Z-hydroxybenzamide ethobromide, N [2 (2 methyl 1 piperidyl) ethyl]-4-nitro-2-hydroxybenzamide benzochloride, N -[3- (l-morpholinyl) propyl] 4 nitro-2- hydroxybenzamide methosulfate and N-[2-(2,5- dimethyl-1-pyrroliclyl) ethyl] -4-nitro-2-hydr0xybenzamide metho-p-toluenesulfate.

EXAMPLE 10 N-(Z-diethylamz'noethyl) 4 nitro-Z-n-propomybenzmmz'de methiodz'de When the procedure described for Example 9 was followed but substituting 6.0 g. of N-(2- diethylaminoethyl) 4 nitro 2-n-propoxybenzamide for the corresponding 2-n-butoxybenzamide, there was obtained N-(Z-diethylaminoethyl) -4-nitro-2-npropoxybenzamide methiodide, M, P. 169.8-1705" C, (con).

AnaL-Calcd for C16H25N3O4.CH3IZ Nmo 3.01; I, 27.28. Found: Nmo 3.05; I, 27.28.

We claim:

1. A member of the group consisting of an N- (tertiary-aminoalkyl) 2 substituted 4 nitrobenzamide having the formula where X is a lower alkylene radical having from 2 to 4 carbon atoms and having its two free valence bonds on different carbon atoms, and R and R1 are each lower alkyl radicals.

3. A compound according to claim 2 where NRR1 is diethylamino.

4, An N- (dialkylaminoalkyl) -4-nitro-2-all oxybenzamide having the formula where X is a lower alkylene radical having from 2 to 4 carbon atoms and having its two free valence bonds on difieretn carbon atoms, and R, R1 and R2 are each lower alkyl radicals.

5. A compound according to claim 4 where NRR1 is diethylamino.

6. A lower alkyl halide quaternary ammonium salt of the compound according to claim 4.

7. N -(2-diethylaminoethyl) 4 nitro 2 hydroxybenzamide.

8. N-(2diethylaminoethyl) 4 nitro-2-methoxybenzamide.

9. N -(2-diethylaminoethyl) 4 nitro-Z-n-butoxybenzamide.

10. An N-(Z-diethylaminoethyl) 4 nitro-2-nbutoxybenzamide methohalide.

11. An N-(2-diethylaminoethyl) 4 nitro-2-npropoxybenzamide methohalide.

References Cited in the file of this patent UNITED STATES PATENTS Name Date Steiger May 8, 1951 Number 

1. A MEMBER OF THE GROUP CONSISTING OF AN N(TERTIARY-AMINOALKYL) -2-SUBSTITUTED-4-NITROBENZAMIDE HAVING THE FORMULA
 4. AN N-(DIALKYLAMINOALKYL)-4-NITRO-2-ALKOXYBEZAMIDE HAVING THE FORMULA 